Cocrystals, Salts, and Supramolecular Gels of Nonsteroidal Anti-Inflammatory Drug Niflumic Acid

Abstract

Niflumic acid (NFA) is a nonsteroidal anti-inflammatory drug (NSAID) classified under the BCS (Biopharmaceutical Classification System) Class II category of poor aqueous solubility and high permeability. In an attempt to improve the physicochemical properties of NFA, particularly solubility and dissolution rate by cocrystallization and salt formation, cocrystals of NFA were prepared with caprolactam (CPR, 1:1) and 2-hydroxy pyridine (2HP, 1:1) as well as salts with piperazine (PIP, 1:0.5), benzenesulfonic acid (BSA, 1:1), benzyl amine (BZA, 1:1 and 2:2), and tyramine (TYA, 1:1). The new solid forms were characterized by powder X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry and confirmed by single crystal X-ray diffraction. In the cocrystals NFA–CPR and NFA–2HP, the cyclic amide of the coformer forms a dimer synthon through N–H···O hydrogen bonds and such dimers extend through O–H···O hydrogen bonds. In piperazine, benzyl amine, and tyramine salts, proton transfer occurs from the NFA to the basic nitrogen of the coformer, and in NFA–BSA salt, the proton is transferred from benzenesulfonic acid to the pyridine nitrogen of NFA. In addition to the above salts and cocrystals, supramolecular gels of NFA–PIP and NFA–BZA salts are reported, which were obtained from nitrobenzene, methyl salicylate, menthol, and mesitylene solvents. These gels were studied by rheology. Solubility and dissolution rate of the novel solid forms (NFA–CPR, NFA–PIP, NFA–BSA, and NFA–TYA) in 20% EtOH–water showed the best behavior for NFA–TYA salt with improvement of 42- and 54-times in solubility and dissolution rate compared to the reference drug. The remaining solids such as NFA–PIP, NFA–BSA salts, and NFA–CPR cocrystal exhibited improvement of 39-, 18-, 1.4-times in solubility and 7.8-, 10-, 2-times for dissolution rate.

Mixing Effects on the Ternary Phase Diagram of Cocrystals and Gibbs Formation Energy Calculation

“…Cocrystallization has evolved as a strategy to develop novel solid forms of materials, particularly pharmaceuticals, − agrochemicals, , and other specialty chemicals, , to improve their physicochemical properties such as solubility, dissolution rate, hygroscopicity, stability, and mechanical properties. In this process, a multicomponent crystal, known as a cocrystal, is obtained by molecular mixing of two components, each of which are solid under ambient conditions. , Understanding the thermodynamic properties of a cocrystal is essential to provide insights into its production, stability, and utilization. − While multiple methodologies have been reported for screening and manufacturing of cocrystals, the preparation of cocrystals by slurrying the components in a solvent is still the most widely followed method from the early development to the late phase of production. , Obtaining solubility data during development studies is routine.…”

An NIF-doped ZIF-8 hybrid membrane for continuous antimicrobial treatment

“…Tetracycline demonstrated high antibacterial properties in previous studies. 37 Compared to ZIF-8 and hydrogels, the composite hydrogels have signicantly greater drug loading; as shown in Fig. 4A, compared to the pure hydrogels, crystal ZIF-NIF on the composite hydrogel surfaces has a larger pore size than ZIF-8.…”

Thermal method usage features for multicomponent crystal screening

“…The thermal stability of the substances under study is one of the important conditions for the thermal method use as the identification and preparation techniques of multicomponent crystals. According to the literature data, NLD, LFX, and TYA are thermally stable compounds even after melting, [29][30][31] in contrast to OXL, NFX, and EFX, in which melt is accompanied by decomposition. 29,30 All selected quinolones are refractory compounds relative to TYA.…”